The problem of occasional massive hepatic necrosis following routine general anesthesia is as yet undefined, unpredictable, undiagnoseable, and untreatable. Lack of an animal model of hepatotoxicity with anesthetics such as halothane has been a major impediment. Preliminary work in this laboratory demonstrates that classic centrolobular necrosis can be rountinely produced by clinical concentrations of halothane in rats pretreated with polychlorobiphenyls, and that this is associated with increases in vitro covalent binding of halothane metabolites with microsomal proteins and phospholipids. This model will be studied in detail with reference to specific metabolite binding in vivo and vitro (by use of variously labeled isotopes of halothane); qualitative and quantitative patterns of urinary metabolite excretion; halide content of liver; sex, strain, and species effects; effects on microsomal enzyme pattern; lipoperoxidative mechanisms; survey of other halogenated anesthetics now in clinical use. As this lesion is based on a reactive intermediate mechanism, attempts will be made with free radical scavengers and antioxidants to prevent the disease and treat the model at various stages. Human liver samples obtained at post (viral hepatitis and "halothane" hepatitis) will be surveyed for this mechanism of toxicity by assaying for products of reactive intermediate damage (diene conjugates, lipofuscin pigments, etc) and halide content in order to develop a differential diagnosis between the two entities.